(a) Field of the Invention
This invention relates to novel 2-substituted-3-methyl-.gamma.-pyrone tricyclic derivatives, to processes for their preparation, to methods for using said derivatives, and to pharmaceutically acceptable compositions of said derivatives.
More specifically, the present invention relates to novel 2-substituted-3-methyl-.gamma.-pyrone tricyclic derivatives possessing valuable pharmacologic properties. For example, these derivatives are useful for treating allergic conditions at dosages which do not elicit undesirable side effects. The combination of these pharmacologic properties together with a low order of toxicity render the 2-substituted-3-methyl-.gamma.-pyrone tricyclic derivatives of the invention therapeutically useful.
(b) Description of the Prior Art
A number of reports dealing with fused .gamma.-pyrone-tricyclic derivatives are available. One report concerns fused .gamma.-pyrone-2-carboxylic acid derivatives of benzofuran, as described by J. B. Wright, U.S. Pat. No. 3,816,467, issued June 11, 1974. Fused .gamma.-pyrone-2-methyl derivatives of benzopyran have been prepared by F. M. Dean, et al., J. Chem. Soc., Chem. Comm., 440(1974), in order to prepare the pyranopyrone nucleus of the fungal metabolite citromycetin. A number of pyrano (3,2-c) (1,2)benzothiazine-6,6-dioxide derivatives are reported by D. Kaminsky et al. in U.S. Pat. No. 3,855,216, issued Dec. 17, 1974. Recently, fused .gamma.-pyrone-3-carboxaldehyde derivatives of dihydroaphthol have been prepared by D. Kaminsky, U.S. Pat. No. 3,862,144, issued Jan. 21, 1975. The compounds of the present invention are distinguished from the prior art compounds by having substituents at a variety of positions on the .gamma.-pyrone tricyclic nucleus, most notably a methyl group at position 3 and a substituent at position 2 as well as having hetero atoms in positions 1 and 6 of the tricyclic nucleus.
In copending U.S. patent application, Ser. No. 649,113, filed Jan. 14, 1976 and now issued as U.S. Pat. No. 4,060,619 on Nov. 29, 1977, .gamma.-pyrone tricyclic derivatives, which differ most notably from the compounds of this invention by lacking a methyl substituent at position C-3 of the tricyclic system, are disclosed. In addition, it should be noted that the use of the processes described therein, with appropriately substituted reactants to obtain the compounds of the present invention, is not suitable for preparing the present compounds, since the required substituted reactants cannot be obtained in practical yields.
Furthermore, a noteworthy feature of the present process involves a novel reaction for converting a .gamma.-pyrone derivative with a functionality at C-3 into a derivatives functionalized at C-2. The reaction comprises an allylic type of rearrangement which occurs when the active ester portion, i.e. the 3-chloromethyl, 3-bromomethyl, 3-fluoromethyl or mesylated hydroxy methyl portion, reacts with cyanide ion whereby functionality at C-2 is introduced. In the field of heterocyclic chemistry in which oxygen is the sole heteroatom of the ring system this type of reaction is unknown.